[(1H-indol-5-yl)-heteroaryloxy]-1-aza-bicylco[3.3.1]nonanes as cholinergic ligands of the n-AChR for the treatment of psychotic and neurodegenerative disorders

ABSTRACT

The present invention relates to 1-aza-bicycloalkyl derivatives of Formula (I) 
                         
wherein the substituents are as defined in the specification and to processes for their production, their use as pharmaceuticals and to pharmaceutical compositions comprising them.

This application is the National Stage of Application No.PCT/EP2006/012023, filed on Dec. 14, 2006, which claims benefit under 35U.S.C. §119(a)-(d) or (f) or 365(b) of GB Application No. 0525672.2,filed Dec. 16, 2005, the contents of which are incorporated herein byreference in their entirety.

The present invention relates to novel 1-aza-bicyclononane derivatives,to processes for their production, their use as pharmaceuticals and topharmaceutical compositions comprising them.

More particularly the present invention provides in a first aspect, acompound of formula (I)

whereinX represents hydrogen or hydroxyl andY represents one of the following groups:

in free base or acid addition salt form.

A preferred compound according to the invention is(4S,5R)-4-[5-(1H-indol-5-yl)-pyrimidin-2-yloxy]-1-aza-bicyclo[3.3.1]nonanehaving the formula shown below.

A further preferred compound according to the invention is5-{2-[(4S,5R)-(1-aza-bicyclo[3.3.1]non-4-yl)oxy]-pyrimidin-5-yl}-1,3-dihydro-indol-2-onehaving the formula shown below.

A further preferred compound according to the invention is(4S,5R)-4-[6-(1H-indol-5-yl)pyridin-3-yloxy]-1-aza-bicyclo[3.3.1]nonanehaving the formula shown below.

A further preferred compound according to the invention is(4S,5R)-4-[5-(1H-indol-5-yl)pyridin-2-yloxy]-1-aza-bicyclo[3.3.1]nonanehaving the formula shown below.

A further preferred compound according to the invention is(4S,5R)-4-[6-(1H-indol-5-yl)pyridazin-3-yloxy]-1-aza-bicyclo[3.3.1]nonanehaving the formula shown below.

A further preferred compound according to the invention is5-{6-[(4S,5R)-(1-aza-bicyclo[3.3.1]non-4-yl)oxy]-pyridazin-3-yl}-1,3-dihydro-indol-2-onehaving the formula shown below.

Compounds of formula (I) exist in free or acid addition salt form. Inthis specification, unless otherwise indicated, language such as“compounds of formula (I)” is to be understood as embracing thecompounds in any form, for example free base or acid addition salt form.Salts which are unsuitable for pharmaceutical uses but which can beemployed, for example, for the isolation or purification of freecompounds of formula (I), such as picrates or perchlorates, are alsoincluded. For therapeutic use, only pharmaceutically acceptable salts orfree compounds are employed (where applicable in the form ofpharmaceutical preparations), and are therefore preferred.

Compounds of formula (I) may exist in form of various isomers, e.g.keto-enol tautomers. In this specification, unless otherwise indicated,language such as “compounds of formula (I)” is to be understood asembracing the compounds in any form, for example in the keto or in theenol form or any mixture of them

Where the plural form is used for compounds, salts, and the like, thisis taken to mean also a single compound, salt, or the like.

In a further aspect, the present invention also provides processes forthe production of compounds of formula (I).

A first process comprises the steps of

i) reacting a compound of formula (IX)

wherein Y is as defined above and Z z represents a leaving group, suchas Cl, Br, I, Tosylatewith a compound of formula (X)

where R represents H, C₁-C₄alkyl or both RO represent together with theB to which they are attached a heterocyclic moiety, X is as definedabove, andii) recovering the so obtained compound of formula (I)

A second process comprises the steps of

i) reacting a compound of formula (XI)

with a compound of formula XII

wherein X and Y are as defined above and PG is a suitable protectinggroup,ii) subsequent deprotection of the so obtained compound andiii) recovering the so obtained compound of formula (I) in free base oracid addition salt form.

This process is particular suitable wherein Y represents the 3-pyridylmoiety.

Starting materials are known or may be obtained by well known processes.The synthesis of the starting materials is described e.g in GB 123456,which is hereby incorporated by reference.

The following considerations apply to the individual reaction stepsdescribed above:

a) One or more functional groups, for example carboxy, hydroxy, amino,or mercapto, may need to be protected in the starting materials byprotecting groups. The protecting groups employed may already be presentin precursors and should protect the functional groups concerned againstunwanted secondary reactions, such as acylations, etherifications,esterifications, oxidations, solvolysis, and similar reactions. It is acharacteristic of protecting groups that they lend themselves readily,i.e. without undesired secondary reactions, to removal, typically bysolvolysis, reduction, photolysis or also by enzyme activity, forexample under conditions analogous to physiological conditions, and thatthey are not present in the end-products. The specialist knows, or caneasily establish, which protecting groups are suitable with thereactions mentioned hereinabove and hereinafter. The protection of suchfunctional groups by such protecting groups, the protecting groupsthemselves, and their removal reactions are described for example instandard reference works, such as J. F. W. McOmie, “Protective Groups inOrganic Chemistry”, Plenum Press, London and New York 1973, in T. W.Greene, “Protective Groups in Organic Synthesis”, Wiley, New York 1981,in “The Peptides”; Volume 3 (editors: E. Gross and J. Meienhofer),Academic Press, London and New York 1981, in “Methoden der organischenChemie” (Methods of organic chemistry), Houben Weyl, 4th edition, Volume15/I, Georg Thieme Verlag, Stuttgart 1974, in H.-D. Jakubke and H.Jescheit, “Aminosäuren, Peptide, Proteine” (Amino acids, peptides,proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982, andin Jochen Lehmann, “Chemie der Kohlenhydrate: Monosaccharide undDerivate” (Chemistry of carbohydrates: monosaccharides and derivatives),Georg Thieme Verlag, Stuttgart 1974.

b) Acid addition salts may be produced from the free bases in knownmanner, and vice-versa. Alternatively, optically pure starting materialscan be used. Suitable acid addition salts for use in accordance with thepresent invention include for example the hydrochloride.

c) Stereoisomeric mixtures, e.g. mixtures of diastereomers, can beseparated into their corresponding isomers in a manner known per se bymeans of suitable separation methods. Diastereomeric mixtures forexample may be separated into their individual diastereomers by means offractionated crystallization, chromatography, solvent distribution, andsimilar procedures. This separation may take place either at the levelof a starting compound or in a compound of formula I itself. Enantiomersmay be separated through the formation of diastereomeric salts, forexample by salt formation with an enantiomer-pure chiral acid, or bymeans of chromatography, for example by HPLC, using chromatographicsubstrates with chiral ligands. Alternatively, optically pure startingmaterials can be used.

d) Suitable diluents for carrying out the above-described are especiallyinert organic solvents. These include, in particular, aliphatic,alicyclic or aromatic, optionally halogenated hydrocarbons, such as, forexample, benzine, benzene, toluene, xylene, chlorobenzene,dichlorobenzene, petroleum ether, hexane, cyclohexane, dichloromethane,chloroform, carbon tetrachloride; ethers, such as diethyl ether,diisopropyl ether, dioxane, tetrahydrofuran or ethylene glycol dimethylether or ethylene glycol diethyl ether; ketones, such as acetone,butanone or methyl isobutyl ketone; nitriles, such as acetonitrilepropionitrile or butyronitrile; amides, such as N,N-dimethylformamide,N,N-dimethylacetamide, N-methyl-formanilide, N-methyl-pyrrolidone orhexamethylphosphoric triamide; esters, such as methyl acetate or ethylacetate, sulphoxides, such as dimethyl sulphoxide, alcohols, such asmethanol, ethanol, n- or i-propanol, ethylene glycol monomethyl ether,ethylene glycol monoethyl ether, diethyelene glycol monomethyl ether,diethylene glycol monoethyl ether. Further, mixtures of diluents may beemployed. Depending on the starting materials, reaction conditions andauxiliaries, water or diluents containing water may be suitable. It isalso possible to use one a starting material as diluent simultaneously.

e) Reaction temperatures can be varied within a relatively wide range.In general, the processes are carried out at temperatures between 0° C.and 150° C., preferably between 10° C. and 120° C. Deprotonationreactions can be varied within a relatively wide range. In general, theprocesses are carried out at temperatures between −150° C. and +50° C.,preferably between −75° C. and 0° C.

f) The reactions are generally carried out under atmospheric pressure.However, it is also possible to carry out the processes according to theinvention under elevated or reduced pressure—in general between 0.1 barand 10 bar.

g) Starting materials are generally employed in approximately equimolaramounts. However, it is also possible to use a relatively large excessof one of the components. The reaction is generally carried out in asuitable diluent in the presence of a reaction auxiliary, and thereaction mixture is generally stirred at the required temperature for anumber of hours.

h) Working up the reaction mixtures according to the above processes andpurification of the compounds thus obtained may be carried out inaccordance to known procedures (cf. the Preparation Examples).

The compounds of the invention, exhibit valuable pharmacologicalproperties when tested in vitro and in animals, and are therefore usefulas pharmaceuticals.

Thus, the compound of the invention are found to be cholinergic ligandsof the nAChR. In addition preferred compound of the invention showselective α7-nAChR activity. The compounds of the present invention mayin particular be found to be agonists, partial agonists, antagonists orallosteric modulators of the receptor.

Due to their pharmacological profiles, compound of the invention areanticipated to be useful for the treatment of diseases or conditions asdiverse as CNS related diseases, PNS related diseases, diseases relatedto inflammation, pain and withdrawal symptoms caused by an abuse ofchemical substances. Diseases or disorders related to the CNS includegeneral anxiety disorders, cognitive disorders, learning and memorydeficits and dysfunctions, Alzheimer's disease (AD), prodromal AD, mildcognitive impairment in the elderly (MCI), amnestic MCI, age associatedmemory impairment, attention deficit and hyperactivity disorder (ADHD),Parkinson's disease, Huntington's disease, ALS, prionicneurodegenerative disorders such as Creutzfeld-Jacob disease and kurudisease, Gilles de la Tourette's syndrome, psychosis, depression anddepressive disorders, mania, manic depression, schizophrenia, thecognitive deficits in schizophrenia, obsessive compulsive disorders,panic disorders, eating disorders, narcolepsy, nociception,AIDS-dementia, senile dementia, mild cognitive dysfunctions related toage, autism, dyslexia, tardive dyskinesia, epilepsy, and convulsivedisorders, post-traumatic stress disorders, transient anoxia,pseudodementia, pre-menstrual syndrome, late luteal phase syndrome,chronic fatigue syndrome and jet lag. Furthermore, compound of theinvention may be useful for the treatment of endocrine disorders, suchas thyrotoxicosis, pheochromocytoma, hypertension and arrhythmias aswell as angina pectoris, hyperkinesia, premature ejaculation anderectile difficulty. Still further, compound of the invention may beuseful in the treatment of inflammatory disorders (Wang et al., Nature2003, 421, 384; de Jonge et al., Nature Immunology 2005, 6, 844; Saeedet al., JEM 2005, 7, 1113), disorders or conditions includinginflammatory skin disorders, rheumatoid arthritis, post-operative ileus,Crohn's disease, inflammatory bowel disease, ulcerative colitis, sepsis,fibromyalgia, pancreatitis and diarrhoea. Compound of the invention mayfurther be useful for the treatment of withdrawal symptoms caused bytermination of the use of addictive substances, like heroin, cocaine,tobacco, nicotine, opioids, benzodiazepines and alcohol. Finally,compound of the invention may be useful for the treatment of pain, e.g.caused by migraine, postoperative pain, phantom limb pain or painassociated with cancer. The pain may comprise inflammatory orneuropathic pain, central pain, chronic headache, pain related todiabetic neuropathy, to post therapeutic neuralgia or to peripheralnerve injury.

Furthermore, degenerative ocular disorders which may be treated includeocular diseases which may directly or indirectly involve thedegeneration of retinal cells, including ischemic retinopathies ingeneral, anterior ischemic optic neuropathy, all forms of opticneuritis, age-related macular degeneration (AMD), in its dry forms (dryAMD) and wet forms (wet AMD), diabetic retinopathy, cystoid macularedema (CME), retinal detachment, retinitis pigmentosa, Stargardt'sdisease, Best's vitelliform retinal degeneration, Leber's congenitalamaurosis and other hereditary retinal degenerations, pathologic myopia,retinopathy of prematurity, and Leber's hereditary optic neuropathy.

It has been found that the effect of a combination which comprises atleast one nicotinic-alpha 7 receptor agonist and at least one compoundselected from the group consisting of (a) conventional antipsychoticsand (b) atypical antipsychotics is greater than the additive effect ofthe combined drugs in the treatment of psychiatric disorders. Inparticular, the combinations disclosed herein can be used to treatschizophrenia which is refractory to monotherapy employing one of thecombination partners alone.

Hence, the invention relates to a combination, such as a combinedpreparation or pharmaceutical composition, which comprises at least onenicotinic-alpha 7 receptor agonist and at least one compound selectedfrom the group consisting of (a) conventional antipsychotics and (b)atypical antipsychotics, in which the active ingredients are present ineach case in free form or in the form of a pharmaceutically acceptablesalt and optionally at least one pharmaceutically acceptable carrier;for simultaneous, separate or sequential use.

The term “psychiatric disorders” as used herein includes, but is notlimited to schizophrenia, anxiety disorders, depression and bipolardisorders. Preferably, the psychiatric disorder to be treated with thecombination disclosed herein is schizophrenia, more preferablyschizophrenia which is refractory to monotherapy employing one of thecombination partners alone. The term “conventional antipsychotics” asused herein includes, but is not limited to haloperidol, fluphenazine,thiotixene and flupentixol.

The term “atypical antipsychotics” as used herein includes, but is notlimited to clozaril, risperidone, olanzapine, quetiapine, ziprasidoneand aripiprazol.

In another aspect, the compound of the invention are used as diagnosticagents and/or PET ligands, e.g. for the identification and localizationof nicotine receptors in various tissues. Properly isotope-labeledagents of the invention exhibit valuable properties as histopathologicallabeling agents, imaging agents and/or biomarkers, hereinafter“markers”, for the selective labeling of the nAChR. More particularlythe agents of the invention are useful as markers for labeling thealpha7 nAChR receptors in vitro or in vivo. In particular, compound ofthe invention which are properly isotopically labeled are useful as PETmarkers. Such PET markers are labeled with one or more atoms selectedfrom the group consisting of ¹¹C, ¹³N, ¹⁵O, ¹⁸F.

The agents of the invention are therefore useful, for instance, fordetermining the levels of receptor occupancy of a drug acting at thenAChR, or diagnostic purposes for diseases resulting from an imbalanceor dysfunction of nAChR, and for monitoring the effectiveness ofpharmacotherapies of such diseases.

In accordance with the above, the present invention provides an agent ofthe invention for use as a marker for neuroimaging.

In a further aspect, the present invention provides a composition forlabeling brain and peripheral nervous system structures involving nAChRin vivo and in vitro comprising an agent of the invention.

In still a further aspect, the present invention provides a method forlabeling brain and peripheral nervous system structures involving nAChRin vitro or in vivo, which comprises contacting brain tissue with anagent of the invention.

The method of the invention may comprise a further step aimed atdetermining whether the agent of the invention labeled the targetstructure. Said further step may be effected by observing the targetstructure using positron emission tomography (PET) or single photonemission computed tomography (SPECT), or any device allowing detectionof radioactive radiations.

In particular, the agents of the invention are α7 nicotinicacetylcholine receptor (αnAChR α7) agonists.

In functional assays, the agents of the invention display high affinityat the nAChR α7 as shown in the following tests:

a) A functional assay for affinity at the nAChR α7 is carried out with arat pituitary cell line stably expressing the nAChR α7. Briefly, GH3cells recombinantly expressing the nAChR α7 were seeded 72 h prior tothe experiment on black 96-well plates and incubated at 37° C. in ahumidified atmosphere (5% CO₂/95% air). On the day of the experimentmedium was removed by flicking the plates and replaced with 100 μlgrowth medium containing af fluorescent calcium sensitive dye, in thepresence of 2.5 mM probenecid (Sigma). The cells were incubated at 37°C. in a humidified atmosphere (5% CO₂/95% air) for 1 h. Plates wereflicked to remove excess of Fluo-4, washed twice with Hepes-bufferedsalt solution (in mM: NaCl 130, KCl 5.4, CaCl₂2, MgSO₄ 0.8, NaH₂PO₄ 0.9,glucose 25, Hepes 20, pH 7.4; HBS) and refilled with 100 μl of HBScontaining antagonists when appropriate. The incubation in the presenceof the antagonist lasted between 3 and 5 minutes. Plates were thenplaced into an imaging plate reader and fluorescence signal recorded Inthis assay, compound of the invention exhibit pEC₅₀ values of about 5 toabout 9. Partial and potent agonists in this test are preferred.

b) To assess the antagonist activity of the compound of the invention onthe human neuronal nAChR α4β2, a similar functional assay is carried outusing a human epithelial cell line stably expressing the human α4β2subtype (Michelmore et al., Naunyn-Schmiedeberg's Arch. Pharmacol.(2002) 366, 235) In this assay, the preferred compounds of the inventionshow selectivity for the nAChR α7 subtype.

c) To assess the antagonist activity of the compound of the invention onthe “ganglionic subtype” (α3β4), the muscle type of nicotinic receptor(α1β1γδ) and the 5-HT₃ receptor, similar functional tests as justdescribed under a) are carried out with a human epithelial cell linestably expressing the human ganglionic subtype, a cell line endogenouslyexpressing the human muscle type of nicotinic receptors or a cell lineendogenously expressing the murine 5-HT₃ receptor (Michelmore et al.,Naunyn-Schmiedeberg's Arch. Pharmacol. (2002) 366, 235). Compounds whichdisplay little or no activity on the α3β4 nAChR, the muscle subtype ofnicotinic receptor as well as the 5-HT₃ receptor are especiallypreferred.

In the model of mice showing sensory gating deficit (DBA/2-mice)described by S. Leonard et al. in Schizophrenia Bulletin 22, 431-445(1996), the compound of the invention induce significant sensory gatingat concentrations of about 10 to about 40 μM.

The compound of the invention may be shown to increase attention in atest of attention for rodents (Robbins, J. Neuropsychiatry Clin.Neurosci. (2001) 13, 326-35), namely the 5-choice serial reaction timetest (5-CSRTT). In this test, the rat must observe a wall containing 5holes. When a light flash appears in one of them, the rat must respondwith a nose-poke into the correct hole within 5 sec. in order to receivea food pellet reward, delivered to a feeder in the opposite wall.

Compound of the invention may also show learning/memory enhancingeffects in the social recognition and in the object recognition test inmice and rats (Ennaceur and Delacour, Behav. Brain Res. (1988) 31,47-59).

The compound of the invention are therefore useful for the preventionand treatment (including mitigation and prevention) of variousdisorders, especially those mentioned above. The usefulness of nAChR α7agonists in neurodegeneration is documented in the literature, e.g. inWang et al., J. Biol. Chem. 275, 5626-5632 (2000).

For the treatment of the above and other disorders, the appropriatedosage of a compound (active ingredient) of the invention will, ofcourse, vary depending upon, for example, the host, the mode ofadministration and the nature and severity of the condition beingtreated as well as the relative potency of the particular agent of theinvention employed. For example, the amount of active agent required maybe determined on the basis of known in vitro and in vivo techniques,determining how long a particular active agent concentration in theblood plasma remains at an acceptable level for a therapeutic effect. Ingeneral, satisfactory results in animals are indicated to be obtained atdaily dosages of from about 0.01 to about 30.0 mg/kg p.o. In humans, anindicated daily dosage is in the range of from about 0.7 to about 1400mg/day p.o., e.g. from about 50 to 200 mg (70 kg man), convenientlyadministered once or in divided doses up to 4× per day or in sustainedrelease form. Oral dosage forms accordingly suitably comprise from about1.75 or 2.0 to about 700 or 1400 mg of a compound of the inventionadmixed with an appropriate pharmaceutically acceptable diluent orcarrier therefore.

Pharmaceutical compositions contain, for example, from about 0.1% toabout 99.9%, preferably from about 20% to about 60%, of the activeingredient(s).

Examples for compositions comprising a compound of the inventioninclude, for example, a solid dispersion, an aqueous solution, e.g.containing a solubilising agent, a microemulsion and a suspension of,e.g. a salt of a compound of formula I or a free compound of the formulaI in the range of from 0.1 to 1%, e.g. 0.5%. The composition may bebuffered to a pH in the range of, e.g. from 3.5 to 9.5, e.g. to pH 4.5,by a suitable buffer.

The compound of the invention are also commercially useful as researchchemicals.

For use according to the invention, a compound of the formula I and/or apharmaceutically acceptable salt thereof may be administered as singleactive agent or in combination with one or more other active agents ofthe formula I and/or a pharmaceutically acceptable salt thereof orespecially other active agents commonly employed especially for thetreatment of the disorders mentioned herein or further other disorders,in any customary manner, e.g. orally, for example in the form oftablets, capsules, or as nasal spray, or parenterally, for example inthe form of injection solutions or suspensions. The other active agentsemployed in such combinations are preferably selected from the groupconsisting of benzodiazepines, selective serotonin reuptake inhibitors(SSRIs), selective serotonin and norepinephrine reuptake inhibitors(SNRIs), conventional antipsychotics, atypical antipsychotics,buspirone, carbamazepine, oxcarbazepine, gabapentin and pregabalin.

An SSRI suitable for the present invention is especially selected fromfluoxetine, sertraline, paroxetine, citalopram and escitalopram. An SNRIsuitable for the present invention is especially selected fromvenlafaxine and duloxetine. The term “benzodiazepines” as used hereinincludes, but is not limited to clonazepam, diazepam and lorazepam. Theterm “conventional antipsychotics” as used herein includes, but is notlimited to haloperidol, fluphenazine, thiotixene and flupentixol. Theterm “atypical antipsychotics” as used herein relates to clozaril,risperidone, olanzapine, quetiapine, ziprasidone and aripiprazol.

Buspirone can be administered in free form or as a salt, e.g. as itshydrochloride, e.g., in the form as marketed, e.g. under the trademarkBuspar™ or Bespar™. It can be prepared and administered, e.g., asdescribed in U.S. Pat. No. 3,717,634. Fluoxetine can be administered,e.g., in the form of its hydrochloride as marketed, e.g. under thetrademark Prozac™. It can be prepared and administered, e.g., asdescribed in CA 2002182. Paroxetine((3S,4R)-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)piperidine)can be administered, e.g., in the form as marketed, e.g. under thetrademark Paxil™. It can be prepared and administered, e.g., asdescribed in U.S. Pat. No. 3,912,743. Sertraline can be administered,e.g., in the form as marketed, e.g. under the trademark Zoloft™. It canbe prepared and administered, e.g., as described in U.S. Pat. No.4,536,518. Clonazepam can be administered, e.g., in the form asmarketed, e.g. under the trademark Antelepsin™. Diazepam can beadministered, e.g., in the form as marketed, e.g. under the trademarkDiazepam Desitin™. Lorazepam can be administered, e.g., in the form asmarketed, e.g. under the trademark Tavor™. Citalopram can beadministered in free form or as a salt, e.g. as its hydrobromide, e.g.,in the form as marketed, e.g. under the trademark Cipramil™.Escitalopram can be administered, e.g., in the form as marketed, e.g.under the trademark Cipralex™. It can be prepared and administered,e.g., as described in AU623144. Venlafaxine can be administered, e.g.,in the form as marketed, e.g. under the trademark Trevilor™. Duloxetinecan be administered, e.g., in the form as marketed, e.g. under thetrademark Cymbalta™. It may be prepared and administered, e.g., asdescribed in CA 1302421. Carbamazepine can be administered, e.g., in theform as marketed, e.g. under the trademark Tegretal™ or Tegretol™.Oxcarbazepine can be administered, e.g., in the form as marketed, e.g.under the trademark Trileptal™. Oxcarbazepine is well known from theliterature [see for example Schuetz H. et al., Xenobiotica (GB), 16 (8),769-778 (1986)]. Gabapentin can be administered, e.g., in the form asmarketed, e.g. under the trademark Neurontin™. Haloperidol can beadministered, e.g., in the form as marketed, e.g. under the trademarkHaloperidol STADA™. Fluphenazine can be administered, e.g., in the formof its dihydrochloride as marketed, e.g. under the trademark Prolixin™.Thiothixene can be administered, e.g., in the form as marketed, e.g.under the trademark Navane™. It can be prepared, e.g., as described inU.S. Pat. No. 3,310,553. Flupentixol can be administered for instance inthe form of its dihydrochloride, e.g., in the form as marketed, e.g.under the trademark Emergil™ or in the form of its decanoate, e.g., inthe form as marketed, e.g. under the trademark Depixol™. It can beprepared, e.g., as described in BP 925,538. Clozaril can beadministered, e.g., in the form as marketed, e.g. under the trademarkLeponex™. It can be prepared, e.g., as described in U.S. Pat. No.3,539,573. Risperidone can be administered, e.g., in the form asmarketed, e.g. under the trademark Risperdal™. Olanzapine can beadministered, e.g., in the form as marketed, e.g. under the trademarkZyprexa™. Quetiapine can be administered, e.g., in the form as marketed,e.g. under the trademark Seroquel™. Ziprasidone can be administered,e.g., in the form as marketed, e.g. under the trademark Geodon™. It canbe prepared, e.g., as described in GB 281,309. Aripiprazole can beadministered, e.g., in the form as marketed, e.g. under the trademarkAbilify™. It can be prepared, e.g., as described in U.S. Pat. No.5,006,528.

The structure of the active ingredients identified by code nos., genericor trade names may be taken from the actual edition of the standardcompendium “The Merck Index” or from databases, e.g. PatentsInternational (e.g. IMS World Publications). The corresponding contentthereof is hereby incorporated by reference. Any person skilled in theart is fully enabled to identify the active ingredients and, based onthese references, likewise enabled to manufacture and test thepharmaceutical indications and properties in standard test models, bothin vitro and in vivo.

In the case of a combination, the pharmaceutical compositions forseparate administration of the combination partners and/or those foradministration in a fixed combination, i.e. a single galenicalcomposition comprising at least two combination partners, according tothe invention can be prepared in a manner known per se and are thosesuitable for enteral, such as oral or rectal, and parenteraladministration to mammals, including man, comprising a therapeuticallyeffective amount of at least one pharmacologically active combinationpartner alone or in combination with one or more pharmaceuticallyacceptable carriers, especially suitable for enteral or parenteralapplication. When the combination partners employed are applied in theform as marketed as single drugs, their dosage and mode ofadministration can take place in accordance with the informationprovided on the packet leaflet of the respective marketed drug in orderto result in the beneficial effect described herein, if not mentionedherein otherwise.

Pharmaceutical preparations for the combination therapy for enteral orparenteral administration are, for example, those in unit dosage forms,such as sugar-coated tablets, tablets, capsules or suppositories, orfurthermore ampoules. If not indicated otherwise, these are prepared ina manner known per se, for example by means of conventional mixing,granulating, sugar-coating, dissolving or lyophilizing processes. Itwill be appreciated that the unit content of a combination partnercontained in an individual dose of each dosage form need not in itselfconstitute an effective amount since the necessary effective amount caninstead with a single dosage unit also be reached by administration of atwo or more dosage units.

In particular, a therapeutically effective amount of each of thecombination partners may be administered simultaneously or sequentiallyand in any order, and the components may be administered separately(e.g. sequentially after fixed or variable periods of time), or as afixed combination. For example, the method of treatment (includingmitigation) of a disorder according to the invention may comprise (i)administration of the combination partner (a) (a compound of the presentinvention) in free or pharmaceutically acceptable salt form and (ii)administration of a combination partner (b) (e.g. a different compoundof the present invention or an active ingredient of a different formula)in free or pharmaceutically acceptable salt form, simultaneously orsequentially in any order, in jointly therapeutically effective amounts,preferably in synergistically effective amounts, e.g. in daily dosagescorresponding to the amounts described herein. The individualcombination partners can be administered separately at different timesduring the course of therapy or concurrently in divided or singlecombination forms. Furthermore, the term “administering” alsoencompasses the use of a prodrug of a combination partner that convertin vivo to the combination partner as such. The instant invention istherefore to be understood as embracing all such regimes of simultaneousand/or alternating treatment and the term “administering” is to beinterpreted accordingly.

The effective dosage of the combination partners employed may vary, forexample depending on the particular compound or pharmaceuticalcomposition employed, the mode of administration, the disorder beingtreated, and/or the severity of the disorder being treated. Thus, thedosage regimen is selected in accordance with a variety of factorsincluding the route of administration, metabolism by and the renal andhepatic function of the patient. A physician, clinician or veterinarianof ordinary skill can readily determine and prescribe the effectiveamount of the single active ingredients required to prevent, mitigate,counter or arrest the disorder. Optimal precision in achievingconcentration of the active ingredients within the range that yieldsefficacy without toxicity requires a regimen based on the kinetics ofthe active ingredients' availability to target sites.

In accordance with the foregoing, the present invention also provides:

(1) A compound of the formula I, and/or a salt thereof, for use in thediagnostic or therapeutic treatment of a mammal, especially a human;especially for use as an alpha-7 receptor agonist, for example for usein the treatment (including mitigation) of any one or more disorders,especially of any one or more of the particular disorders set forthhereinbefore and hereinafter.

(2) A pharmaceutical composition comprising a compound of the formula I,and/or a pharmaceutically acceptable salt thereof, as active ingredienttogether with a pharmaceutically acceptable diluent or carrier.

(2′) A pharmaceutical composition for the treatment or prevention of adisorder in the treatment of which alpha-7 receptor activation plays arole or is involved and/or in which alpha-7 receptor activity isinvolved, especially any one or more of the disorders mentionedhereinbefore or hereinafter, comprising a compound of the formula I,and/or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable diluent or carrier.

(3) A method for the treatment of a disorder, especially any one or moreof the particular disorders set forth hereinbefore, in a subject in needof such treatment, comprising administering a pharmaceutically effectiveamount of a compound of the formula I, or a pharmaceutically acceptablesalt thereof.

(3′) A method for treating or preventing a disorder in the treatment ofwhich alpha-7 receptor activation plays a role or is involved and/or inwhich alpha-7 receptor activity is involved, comprising administering toa mammal in need thereof a therapeutically effective amount of acompound of the formula I, and/or a pharmaceutically acceptable saltthereof.

(4) The use of a compound of the formula I, and/or a pharmaceuticallyacceptable salt thereof, for the manufacture of a medicament for thetreatment or prevention of a disease or condition in the treatment ofwhich alpha-7 receptor activation plays a role or is involved and/or inwhich alpha-7 receptor activity is involved, especially one or more ofthe disorders mentioned above.

(5) A method as defined above comprising co-administration, e.g.concomitantly or in sequence, of a therapeutically effective amount ofan alpha-7 agonist of the formula I, and/or a pharmaceuticallyacceptable salt thereof, and a second pharmaceutically active compoundand/or a pharmaceutically acceptable salt thereof, said secondpharmaceutically active compound and/or salt thereof being especiallyfor use in the treatment of any one or more of the disorders set forthhereinbefore or hereinafter.

(6) A combination comprising a therapeutically effective amount of analpha-7 agonist of the formula I, and/or a pharmaceutically acceptablesalt thereof, and a second pharmaceutically active compound and/or apharmaceutically acceptable salt thereof, said second pharmaceuticallyactive compound being especially for use or of use in the treatment ofany one or more of the particular disorders set forth hereinbefore.

The Examples which follow serve to illustrate the invention withoutlimiting the scope thereof. The following abbreviations are used:

AcOEt ethyl acetate

aq. aqueous

EtOH ethanol

FC flash chromatography

HV high vacuum

MeOH MeOH

m.p. melting point

MTBE methyl tert-butyl ether

NHMDS sodium hexamethyl disilazane

rt room temperature

soln. solution

THF tetrahydrofuran

Temperatures are measured in degrees Celsius. Unless indicatedotherwise, reactions are carried out at room temperature. The structureof final products, intermediates and starting materials is confirmed bystandard analytical methods, e.g. microanalysis and spectroscopiccharacteristics (e.g. MS, IR, NMR).

EXAMPLE 1

(4S,5R)-4-[5-(1H-Indol-5-yl)-pyrimidin-2-yloxy]-1-aza-bicyclo[3.3.1]nonane1-Aza-bicyclo[3.3.1]nonan-4-one (11.92 g, 85.6 mmol) is dissolved in 160ml MeOH and cooled to −10° C. NaBH₄ (1.69 g, 42.9 mmol)) is addedportionwise so that the inner temperature does not exceed 0° C. Thereaction mixture is stirred at −10° C. for 1 h. Water is added and thesolvents are evaporated. The remaining solid is dissolved in MTBE/MeOH,filtered over hyflo and the filtrate is evaporated to give 19.28 g ofcrude product which is purified by chromatography over aluminum oxide(400 g, eluent: MTBE/MeOH 95:5 to 80:20) to give 10.96 g (91%)(4SR,5RS)-1-aza-bicyclo[3.3.1]nonan-4-ol.

To acetic anhydride (150 ml) (4SR,5RS)-(1-aza-bicyclo[3.3.1]nonan-4-ol(21.34 g, 151 mmol) is added portionwise under cooling. The reactionmixture is heated to 120° C. for 2.5 h, is evaporated and extracted withTHF/sat. K₂CO₃ soln. The aq. layer is reextracted with THF. The combinedorganic layers are washed with brine, dried over Na₂SO₄, filtered andevaporated. The crude product is purified by bulb-to-bulb distillation(HV, 90° C.) to give 24.07 g (87%) of (4SR,5RS)-acetic acid1-aza-bicyclo[3.3.1]non-4-yl ester.

Acetic acid 1-aza-bicyclo[3.3.1]non-4-yl ester (120.0 g, 655 mmol) isdissolved in 200 ml EtOH abs. and 50 ml water. L(+)-tartaric acid (98.3g, 655 mmol) is added and the mixture is heated to reflux for 1 minute.The mixture is cooled to rt, then to 4° C. The precipitate is filteredoff, washed with EtOH, and 3× recrystallized from EtOH/H₂O 4:1 to give41.16 g of the tartrate salt ([α]_(D) ^(rt)=−14.72° (c=0.265, MeOH))which gives after treatment with sat. Na₂CO₃ soln. 22.6 g (123 mmol,19%) (4S,5R)-acetic acid 1-aza-bicyclo[3.3.1]non-4-yl ester as the freebase. Another 10.7 g (32.1 mmol, 5%) of tartrate can be obtained fromthe mother liquors by another 3 recrystallizations from EtOH/H₂O 4:1.

(4S,5R)-acetic acid 1-aza-bicyclo[3.3.1]non-4-yl ester (5.45 g, 29.7mmol) is dissolved in 10% aq. NaOH soln. and stirred for 1 h at 50° C.After cooling to rt, the mixture is extracted with THF/brine. Theorganic layer is dried over Na₂SO₄, filtered and the filtrate isevaporated to give 3.83 g (91%) of(4S,5R)-1-aza-bicyclo[3.3.1]nonan-4-ol, which is dissolved in 50 ml THFand cooled to 0° C. NHMDS (35 ml of 1 M THF soln.) is added dropwise,the reaction mixture is stirred at rt for 0.5 h and then added to aprecooled soln. (−15° C.) of 5-bromo-2-chloro-pyrimidine (5.89 g, 30.5mmol) in THF. The mixture is stirred for 15 h at rt, then diluted withTHF and extracted with 1M aq. NaOH soln. and brine. The aq. layers are2× reextracted with THF, the combined organic layers are dried overNa₂SO₄, filtered and the filtrate is evaporated. The resulting crudeproduct (10.15 g) is recrystallized from CH₃CN/MeOH to give 5.21 g (65%)of (4S,5R)-4-(5-bromo-pyrimidin-2-yloxy)-1-aza-bicyclo[3.3.1]nonane.

5.19 g (17.4 mmol) of(4S,5R)-4-(5-bromo-pyrimidin-2-yloxy)-1-aza-bicyclo[3.3.1]nonane isdissolved in 200 ml toluene/EtOH 9:1. 5-Indolyl boronic acid (3.47 g,21.6 mmol), Pd(PPh₃)₄ (1.04 g, 0.873 mmol) and a soln. of Na₂CO₃ (7.38g, 69.6 mmol) in 35 ml H₂O is added. The reaction mixture is stirred at90° C. for 15 h. After cooling to rt the mixture is filtered over hyflo,the filtrate is extracted with water and brine. The aq. layers arereextracted with AcOEt and the combined organic layers are dried overNa₂SO₄, filtered and the filtrate is evaporated. The resulting crudeproduct is purified by FC (255 g silica gel, eluent AcOEt/MeOH/Et₃N70:27:3) and recrystallization from EtOH to give 3.87 g (67%)(4S,5R)-4-[5-(1H-indol-5-yl)pyrimidin-2-yloxy]-1-aza-bicyclo[3.3.1]nonane.MS (ES⁺): m/e=335 (MH⁺), m.p. 195-199° C.

Preparation of the precursor 1-aza-bicyclo[3.3.1]nonan-4-one is doneaccording to M. G. Kim et al., J. Med. Chem. (2003) 46, 2216.

EXAMPLE 2 Manufacture of Soft Capsules

5000 soft gelatin capsules, each comprising as active ingredient 0.05 gof one of the compounds of formula (I) mentioned in the precedingExamples, are prepared as follows: 250 g of the pulverized activeingredient is suspended in 2 liters Lauroglykol® (propylene glycollaurate, Gattefossé S. A., Saint Priest, France) and ground in a wetpulverizer to produce a particle size of about 1 to 3 μm. 0.419 gportions of the mixture are then introduced into soft gelatin capsulesusing a capsule-filling machine.

1. A compound of formula (I)

wherein X represents hydroxyl, and Y represents one of the followinggroups:

or a tautomer thereof, in free base or acid addition salt form.
 2. Thecompound according to claim 1, wherein the compound is5-{2-[(4S,5R)-(1-Aza-bicyclo[3.3.1]non-4-yl)oxy]-pyrimidin-5-yl}-1,3-dihydro-indol-2-one.3. The compound according to claim 1, wherein the compound is5-{6-[(4S,5R)-(1-Aza-bicyclo[3.3.1]non-4-yl)oxy]-pyridazin-3-yl}-1,3-dihydro-indol-2-one.4. A process for preparation of a compound of formula (I)

wherein X represents hydroxyl, and Y represents one of the followinggroups:

or a tautomer thereof, the process comprising the steps of i) reacting acompound of formula (IX)

wherein Y is defined above and z represents a leaving group, with acompound of formula (X)

where R represents H, C₁-C₄ alkyl or both RO represent together with theB to which they are attached a heterocyclic moiety, and X is definedabove, and ii) recovering the so obtained compound of formula (I).
 5. Aprocess for preparation of a compound of formula (I)

wherein X represents hydroxyl, and Y represents one of the followinggroups:

or a tautomer thereof, the process comprising the steps of i) reacting acompound of formula (XI)

with a compound of formula (XII)

wherein X and Y are defined above and PG is a suitable protecting group,ii) subsequent deprotection of the so obtained compound, and iii)recovering the so obtained compound of formula (I) in free base or acidaddition salt form.
 6. A pharmaceutical composition, comprising: thecompound of claim 1 in free base or pharmaceutically acceptable acidaddition salt form, in association with a pharmaceutical carrier ordiluent.